Diamines



Patented May 18, 1948 YTHQUTNITED STAT Walter F. Holcom Grosse PointePark,

Davis & Company, Det

of Michigan DIAMINES r Detroit, and Leon A; Sweet,

Mich., assignors to Parke,

roit,Mich.,acorporation iv No Drawing." Application August 7, 1 042, i vSerialNo.-i54,064

clai s; (01.260-279) The .inventionrelates to new and-valuabletherapeutic substances and vto a new class of alkylene diaminecompounds. 4

The new products of the inventionhave, for their free base forms, thegeneral formula, a

alkyloxy and Y is an alkylene residue'oi 2 to 12 carbon atoms which maybe interrupted by -O-, -+S'-, -NH- 'N(lower alkylor -N= and may ineither case be substituted on a carbon atom thereof 'by NO2, NI-Iz,NH(lower or Br.

-Examples'oi Y groups are the following:

.Variousnon-toxic inorganic and organic acid addition salts of theaminefree bases described are included in the invention. For examplesalts can beobtained with inorganic acids such as hy- 2 l a The freebaseitself can be obtained by evaporating ofi'the chloroform andfractionally distilling the residue; 10.5 grams of the main fraction,consisting of :a uniform liquid, .are added to'a mixture of '--101g. :oi3,9 dichloro-7-methoiwacridine and g. oi'phenol which mixture has beenpreviously heated on a steam bath for 15 minutes. The3,9-'dichloro-'7-methoxy acridine canbe obtained, for example, asdescribed in U. S. Patent 1,855,302. The mixture of the phenol and thequinoline and acridinecompounds drochloric, sulfuric, phosphoricand'boric acids. 45

Also with'organic acids such as lactic, citric, salicylic, benzoic,naphthoic, nicotinic, maleic and phthalic acids.

tion: 7 a ExcmpleI I The preparation of a chloroform solution of thefree base, 8-7 aminopropylamino-fiemethoxy quinoline, is described byBaldwin'in Journal of the: hem a e y.

The following examples illustrate the inven- [1 92 9,'page 2959 et seq;

o Dihydrochloride is heated on hours. I v a The reaction mixture istaken from the steam bath and treated with 500cc. of 5% sodium hydroxidesolution, the supernatant liquid is decanted ofi and the residue washedonce with 5% sodium hydroxide solution and then washed several timeswith water. The Washed residue is taken up in 300-400 cc. of diethylether, dried over potassium carbonate, filtered, the filtrateconcentrated to cc.,' dried again with potassium carbonate andvfiltered, and the filtrate treated with alcoholic -H0l and a little moreethanol. The bright orange colored solid is filtered ofi and dried. Itmelts at 234-236? Cyand upon recrystallization from cellosolve (ethyleneglycol monoethylether). gives 3 -chloro-7-methoxy 9 -6-methoxy8'-quinolylaminopropylamino) acridine.

The preparation of the products or this example can be illustrated bythe following diagram:

the steam bath :for a period of 4 V or i I Q N CHSO a 7 c1 omo y lEliNNH 7 --2Hc1- Free base The product 01 this example is especiallyvaluable as an antimalarial and has a therapeutic index several timesthat of the known antimalarials. Thejmaximum tolerated dose ior the newproduct; is exceptionally high.

anol has a melting point of .148-150 C. It is the mono-hydrochloride of'3-chloro-7-methoxy- 9(w-6'-methoxy-8-quinolyl aminopentylamino)acridine and its free base has the formula,

The 8-w-aminopentylamino-B methoxy quinoline used in the example may beprepared as described by Baldwin, Journal of the Chemical Society, 1929,page 2959 et seq.-

Example III '6-methoxy-8-(e amino ethyl) amino quinoline is prepared asdescribed by Baldwin (J. Chem. Soc, 1929, p. 2959).. Seven grams of thisquincline compound is added to a mixture of 7.1 g. of3,9-dichloro-7-methoxy acridine and 35 .g. of phenol which has already.been heated on the steambath for 15 minutes. The mixture of thequinoline and acridine compounds is heated on the steambath for hours,thencooled and taken up in 300 cc. of ether. The ether solution iswashed 5 times with. 100 cc.'. portions of 5% sodium hydroxide solutionand twice with water. The ether solution is dried over magnesium sulfateand then evaporated to a volume of about 100 cc. An equal volume ofabsolute ethanol is added and the solution boiled with charcoal andfiltered. Addition of alcoholic'hydrogen chloride to the filtrate givesan orange precipitate. This is-separated and crystallized from methanoland has a meltingpoint oi 234-6 C. (withdecomposition). The compound isa dihydrochloride ofiormula,

ri omoflr -e-i mf Example IV 4 base is taken up in and crystallized fromethanol which contains a little ammonia.

The phthalimido compound, 13.2 g., is refluxed 1 hours with 100 cc. ofethanol and 4 cc. of 85% hydrazine hydrate. The alcohol is evaporated ina stream of air and the residue heated 30 minutes with 250 cc. of 3.2 Nhydrochloric acid. The mixture is cooled and filtered, and the filtrateneutralized with ammonia. The solution is" saturated with potassiumcarbonate and extracted 3 times with 200 cc. portions of chloroform. Thecombined chloroform extracts are 16 Joan. be used "Without furtherpurification.

mixed with 5 cc. of Cellosolve and 15 g. of fi-methoxy-B-amino-quinolineand heated to 125-15 0 for 6 hours with occasional stirring. Thereaction product is ground in a mortar, boiled with 100 cc. of absoluteethanol, and filtered. The free base is liberated by triturationot thehydro.- bromide with 5% sodium carbonate solution; The

dried over potassium carbonate and then evaporated to dryness. The6-methoxy-8-(w-amino butyl) aminoquinoline is a dark viscous oil andmethoxy-8-(w-aminobutyl) -amino quinoline, 7.7 g., is heated 5 hourswith 7.1 g. of 3,9-dichloro-7- methoxy-acridine and 35 g. of phenol. Thereaction mixture is worked up as described for3-chioro-7-methoxy-9(e-W-methoxy-ll'-quinolyl aminoethylamino) acridine.The product crystallizes from methanol asv a yellow solid. It may beobtained in. the form of its free base or as its acid addition saltswith various mineral and organic acids. The product in the form of itsfree base has the formula,

HN-CHgCHzCHgCHwNH CHQO /N\ \N Ci OHELO The dihydrochloride melts at231-233 C. (decomp).

Example V.

A mixture of 100 g. of hexamethylene bromide, 23.2 g. of phthalimide,and 16.6 g; of potassium carbonate is refluxed for 2%; hours. The excesshexamethylene bromide is then removed by distillation with steam. Theresidual oil doesnot solidify, but low melting, solid w-bI'OmO hexylphthalimide is obtained bydissolving theoil in methanol and cooling thesolution in an icebath.

w-Bromohexyl phthalimide, 26 g., is heated with 5 cc. of celiosolve and15 g. of 6-methoxy-8- amino-quinoline for '6 hours at l25-135. Thesemi-solid product is boiled with 100 cc. of ethanol and filtered. Thefree base is liberated by trituration of the hydrobromide with sodiumcarbonate solution. The base is then crystallized from ethanolcontaining a little ammonia. It is w-(6'-methoxy-8-quinolyl amino) hexylphthalimide. This phthalimido compound, 14g, is refluxed ly hours with100 cc. of ethanol and 4 cc. of hydrazine hydrate. The alcohol isevaporated in a stream of air and the residue heated 30 minutes with259cc, of 3.2 N hydrochloric acid. The mixture is cooled and filtered,and the filtrate neutralized with ammonia.- The solution is saturatedwith potassiumcarbonate and extracted 3 times .with 200 cc. portions ofchloroform. The combined extracts are dried over potassium carbonate andevaporated to. dryness. 1 The. 6.-methoxy-8-(w-aminohexyl)aminoquinoline is a viscous oil, and is used directly in the nextreaction. j--

6-methoxy 8 (-w-aminohexyl) -aminol-quino line, 8.8 g., is mixed with .7.1 g. of 3,9-dichlo1o-7- methoxy-acridine and '35 g.'of phenol and themixture heated on the steam bath for 5 hours. Thereaction mixture isworked up as described for 3' e chloro-7- methoxy-Q-iflfi'ymethoxy-yquinolyl amino ethyl'amino) 5 acridine. -The product"crystallizes from methanol as ayellow solid. The free base can bereacted with various organic and inorganic acids to obtain acid additionsalts. The free base"is, 3-chloro-7-methoxy- 9(o-6-methoxy-8'-quinolylaminohexylamino) acridine.

Example VI A mixture of 100 g. oi decamethylene bromide, 18.9 g. ofphthalimide, and 9.5 g. of potassium carbonate is heated to 200 for 2hours. The excess decamethylene bromide is removed by distillation withsteam. The residual oil does not crystallize but can be'directlyused toreact with an amino quinoline.

The oily w-bromodecyl phthalimide, 35 g., is mixed with 5 cc. ofcellosolve and 15 g. of G-methoxy-8-amino-quinoline and heated to125-130 for 6 hours with occasional stirring. The reaction product isboiled with 100cc. of ethanol, then cooled and filtered. Thehydrobromide is triturated with sodium carbonate solution and the freebase crystallized from ethanol which contains a little ammonia. Thephthalimido compound, 16 g., is refluxed for 1 hours with 100 cc. ofethanol and 4 ccfof 85% hydrazine hydrate in order to convert thephthalimido group to an amino group (-NH2). The alcohol is evaporated ina stream of air and the residue heated 30 minutes with 250 cc. of 3.2 Nhydrochloric acid. The mixture is cooled and filtered, and the filtrateneutralized with ammonia. The solution is saturated with potassiumcarbonate and extracted 3 times with 200 cc. portions of chloroform. Thechloroform is dried over magnesium sulfate and evaporated to dryness.The residue, 6-methoxy- 8-(w-aminodecyl) amino-quinoline, is a dark oil.It is used in the next reaction without further purification.

6-methoxy-8 (w-aminodecyl) amino quinoline, 10.7 g., is mixed with 7.1g. of 3,9-dichloro 7-methoxy-acridine and 35 g. of phenol and heated onthe steam bath for 5 hours. The reaction mixture is worked up asdescribed for 3- chloro-7-methoxy-9-(p-6'-methoxy -8'-quinolylamino-ethyl-amino) -acridine. The productcrystallizes frommethanol as a yellow solid. The free base is, a3-chloro-7-methoxy-9(w-W-methe oxy-8'-quinolyl-aminodecylamino)acridine.

Example VII 2-methoxy-7-nitro -9- chloroacridine can be prepared bythemethod of Dhar, Narang and Ray, Journalof the Chemical Society, 304(1938). A solution'of 8.7 g. (0.03 mole) of this compound in 36 g. ofphenol is obtained by'warmlng the two substancestogether on'thesteambath. 6.9 g. (0.03 mole) of S-(v-aminoprQpyIamino) -6-methoxy quinolineare added to the phenol solution of the acridine compound and themixture is heated on the steam bath for a period of .4 hours. Thereaction solution is poured into an excess of "5% sodium hydroxidesolution and'the precipitated gum-like base is extracted'withchloroform. The chloroform extracts are washed successively with dilutesodium hydroxide solution and water and; dried over anhydrous potassiumcarbonate. The dry chloroform solution is filtered off and an excess ofalcoholic hydrogen chloride added. A precipitate of thedihydrochlorideof 2-methoxy-7-nitro-9-[y-(6'-methoxy-'8'-quinolyl'-'amino) -propyl amino]-acridine separates out. It is collected and dried. When recrystallized.from methanol. ethanol or cellosolve, it has a melting point of 242-291C.

Y Example VIII 6 {5. of. the 7-nitro compound obtained in Example VIIare hydrogenated catalytically with Raneyjnickel catalyst in a solutionof boiling alcohol. -When the required amount of hydrogen has beenabsonbed, the catalyst is removed from thereaction mixture byfiltration. The'alcohol is evaporated off and the residue purifiedbyrecrystallization in the form of its hydrochloric acid addition salt.The formula for the free base of this example is, P

HN cH20H2cHz-l?11 Example IX Preparation of2-methoxy-6-nitro-9-ch1oroacridine is described in U. S. Patent1,962,277 (1934) and in British Patent 283,510 (1927). A solution of 8.7g. (0.03 mole) of this acridine compound in 36 g. of phenol is obtainedby warming the two substances together on the steam bath 6.9 g'. (0.03mole) of 8-(Y-aminopropylamino) -'6-methoxy-quinoline are added tothephenol solution of the acridine compound. The mixture is heated on thesteam bath for about 4 hours. and the reaction mixture worked up in amanner analogous to that described for the 7-nitro isomer describedunder Example VII. The free base product is 2-methoxy-6-nitro-9 [Y-(6'-methoxy-'8'-quinolyl amino) -propyl aminol acridine'. The free basemay be reacted with various organic or inorganic acids as alreadydescribed above; I i v Ewample X In this example, the2-methoxy-6-nitro-9- [y-(fi methoxy-s' quinolyl amino) -propyl amino]-acridine of the preceding example is reduced catalytically to thecorresponding 6 -amino compound in the same manner as indicated abovefor the preparation of the 7-arm'no isomer of Example VIII. I Example XIMagidson and Trawin, Ber. 69, p. 537 (1936) and Russian Patent 48,307(1937) describe the preparation of 2-methoxy 6 cyano-9-chloroacridine.8.1 g. (0.03 mole) of this compound are dissolved'in 36 got phenol bywarming the mixture on steam bath. 6.9 g. (0.03 mole) of8-(yaminopropylamino) 6 methoxy quinoline are added to the phenolsolution of the acridine compound and the mixture heated on the steambath for about 4 hours. The reactionproduct is then worked up asindicated for the above described 6-nitro analogue. A high meltinghydrochloride is obtained loyrecrystallization from methanol,

The formula for the-free base product is, V

. V \N -oN c1130 Example XII j lleeidsphg G lfq sk were.) 4: jl fqenl(U. it), 8; 56 (1938*); Chemical Ab stracts, 32, 5465 (1938?, describepreparation of 2 methoxy-G-bromo- 9' chloroacridine. 9.8 g. (0.03 mole)of this compound are dissolved in 36 g. of. phenol by warming on.a steambath 6.9g. (0.03 mole) of 8 (y-aminopropylamino) -6.-meth.-- oxyquinoline are added to the phenol solution of the chloroaeridine. Themixture is heated on the steam bath for about 4- hours: and then worked;upasrdescribed for the G-nitrocompound or Example X. The'high' meltinghydrochloride or sulfate, or other suitable acid addition. salt can be:obtained by recrystallization from methanol, ethanol, or Cellosolve. Thefree base is 2-methoxy-fi-bromo- 9- [y- (6'-methoxy-8' quinolyiamino)-propyl' amino] --a'cridine. It has the formuia,

IIIH

where R, R1, R2, Re and Y have the same sige ni-flcance as given aboveand Hal is a halogen atom.

The use of a phenol when reacting a 9-h-alo-' acridine, such as a9-chloro-acridine, is preferred although not necessary, because yieldsare therebyincreased. Arr intermediate phenolic ether is probably firstformed by reaction of the phenol with the acridine compound prior to thereaction with the mono-heterocyclic substituted diamine.

Other known methods of substituting an amino hydrogen atom of analkylene diamine by a hydrocarbon radical may be used. For example, if75 onefhas a monoqui nolyl' substituted alkylene diarni'nae of formula,

omo

The resulting product has the formula,

The latter product, when treated several hours with a condensing agentsuch as phosphorus oxychloride in an inert solvent gives the followingdiamine, I

7 since We claims I. A. compound of' the class consisting'of diaminesand their acid addition salts with non-- toxic acids; the formula forthe free diamines being where- R is a member of the class consisting of--H, --OH', '--B'r, --NO'2, --NH2 and CN, R1 is a member of the classconsisting of lower aikyl lower alky'l'oxy, hydroxy lower alkyl', andhydro'iry'lo-wer alkyloxy; R2 is a member of the class consisting ofhydrogen and lower alkyl, R3 is a" member of the class consisting ofhydrogen, lower alkyllower alkyloxy, hydroxy lower alkyl and hydroxylower'alkyloxy, and Y is an alkylene residue-oi 2' to 12- carbon atomsof the class con sistingv ot alkyl-ene residue, an alkylene residueinterrupted by a member oi the group consisting of O;-, ..S-- N-I-I',-N(lower aIkyl)', --N=, and such interruptedand uninterrupted alkyleneresidues substituted on a carbon atom thereof by one of the groupconsisting of --N0r,

'NHOH,Z =O, ,-e-C1 and. Br. 2. A compound of 'the'cla'ss' c'onsistin'gof "diamines an'dltheir .acidi'ad'ditionisalts with-hontoxic 'acids,.the .formula.for;the free "diamines being H I e, I j

N g 0.112; N-Rz R1 R -m \N R \J where R is a member of the classconsisting of -H, OH, -Cl, Br, -NOz, NH2 and -CEN, R1 is a member of theclass consisting of lower alkyl, lower alkyloxy, hydroxy lower alkyl,and hydroxy lower alkyloxy, R2 is a member of the class consisting ofhydrogen and lower alkyl, R3 is a member of the class consisting ofhydrogen, lower alkyl, lower alkyloxy, hydroxy lower alkyl and hydroxylower alkyloxy, and n is an integer greater than one and not more than12.

3. A compound of the class consisting of diamines and their acidaddition salts with nontoxic acids, the formula for the free diaminesbeing CHaO where n is an integer greater than one and not more thantwelve.

4. A compound of the 'class consisting of diamines and their acidaddition salts with nontoxic acids, the formula for the free diaminesbeing \N o1 onto 6. A compound of the class consisting of a diamine andits acid addition salts with nontoxic acids, the formula for the freediamine being \N CI 01130 V '7. A compound of the 'class consisting of adiamine and its acid addition salts with non- '10 toxic acids, thelforrnulaf fortm free diamine being 8. Process for the preparation ofdiheterocyclic substituted alkylene diamines which comprises reacting acompound of formula,

r m c1130 with a compound of formula, H2NC Han-NH CHaO where Hal is areactive halogen atom and where n is an integer greater than one and notmore than twelve.

9. Process for the preparation of diheterocyclic substituted alkylenediamines which comprises reacting an acridine compound of formula,

IIIaI omowith a compound of formula,

2N- n 2n1| where n is an integer greater than one and not more thantwelve and R is a member of the class consisting of -H, -OH, Cl, -Br,NOz, NH2 and CEN.

10. Process for the preparation of diheterocyclic substituted alkylenediamines which comprises reacting a compound of formula,

CHZO

with a compound of formula,

HzNC Hz -N| H where n is an integer greater than one and not LEON A.SWEET.

(References on following page) 11 REFERENCES CITED l The followingreferences are of record in the file of this patent:

UNITED STATES PATENTS V 5 Number Name Date 1,747,531 Schulemann Feb. 18,1930 1,757,394 Schulemann May 6, 1930 1,760,781 Schulexhann May 27, 193010 Number Name Date Murri11-.... Apr. 5, 1932 Schulemann Nov. 29, 1932Schule'niann Mar. 28,1933 Jensch Aug. 11,1936 Mietzsch Apr. 13, 1937Hata et a1. June 15, 1937 Clifford Aug. 9, 1938 Kendall Jan. 5, 1943

